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Predictive Performance of Neutrophil Gelatinase Associated Lipocalin, Liver Type Fatty Acid Binding Protein, and Cystatin C for Acute Kidney Injury and Mortality in Severely Ill Patients. Ann. Lab. Med. (IF 4.9) Pub Date : 2023-09-26 Ayu Asakage, Shiro Ishihara, Louis Boutin, François Dépret, Takeshi Sugaya, Naoki Sato, Etienne Gayat, Alexandre Mebazaa, Benjamin Deniau
Acute kidney injury (AKI) is a common condition in severely ill patients associated with poor outcomes. We assessed the associations between urinary neutrophil gelatinase-associated lipocalin (uNGAL), urinary liver-type fatty acid-binding protein (uLFABP), and urinary cystatin C (uCysC) concentrations and patient outcomes.
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Allosteric modulator potentiates β2AR agonist–promoted bronchoprotection in asthma models J. Clin. Invest. (IF 15.9) Pub Date : 2023 Seungkirl Ahn, Harm Maarsingh, Julia K.L. Walker, Samuel Liu, Akhil Hegde, Hyeje C. Sumajit, Alem W. Kahsai, Robert J. Lefkowitz
Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled β2-adrenergic receptor (β2AR) agonists (β2-agonists) promote — with limited efficacy — bronchodilation in asthma. All β2-agonists are canonical orthosteric ligands that bind the same site as endogenous epinephrine. We recently isolated a β2AR-selective positive allosteric modulator (PAM), compound-6 (Cmpd-6)
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AI Chatbots in Clinical Laboratory Medicine: Foundations and Trends Clin. Chem. (IF 9.3) Pub Date : 2023-09-04 He S Yang, Fei Wang, Matthew B Greenblatt, Sharon X Huang, Yi Zhang
Background Artificial intelligence (AI) conversational agents, or chatbots, are computer programs designed to simulate human conversations using natural language processing. They offer diverse functions and applications across an expanding range of healthcare domains. However, their roles in laboratory medicine remain unclear, as their accuracy, repeatability, and ability to interpret complex laboratory
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Reducing Lipid Panel Error Allowances to Improve the Accuracy of Cardiovascular Risk Stratification Clin. Chem. (IF 9.3) Pub Date : 2023-08-25 Justine Cole, Maureen Sampson, Hendrik E van Deventer, Alan T Remaley
Background The standard lipid panel forms the backbone of atherosclerotic cardiovascular disease risk assessment. Suboptimal analytical performance, along with biological variability, could lead to erroneous risk assessment and management decisions. The current National Cholesterol Education Program (NCEP) performance recommendations have remained unchanged for almost 3 decades despite improvements
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Classification of Brain Tumors by Nanopore Sequencing of Cell-Free DNA from Cerebrospinal Fluid Clin. Chem. (IF 9.3) Pub Date : 2023-08-25 Ann-Kristin Afflerbach, Christian Rohrandt, Björn Brändl, Marthe Sönksen, Jürgen Hench, Stephan Frank, Daniela Börnigen, Malik Alawi, Martin Mynarek, Beate Winkler, Franz Ricklefs, Michael Synowitz, Lasse Dührsen, Stefan Rutkowski, Annika K Wefers, Franz-Josef Müller, Melanie Schoof, Ulrich Schüller
Background Molecular brain tumor diagnosis is usually dependent on tissue biopsies or resections. This can pose several risks associated with anesthesia or neurosurgery, especially for lesions in the brain stem or other difficult-to-reach anatomical sites. Apart from initial diagnosis, tumor progression, recurrence, or the acquisition of novel genetic alterations can only be proven by re-biopsies.
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Quantification of Urine and Plasma Porphyrin Precursors Using LC–MS in Acute Hepatic Porphyrias: Improvement in Routine Diagnosis and in the Monitoring of Kidney Failure Patients Clin. Chem. (IF 9.3) Pub Date : 2023-08-23 Antoine Poli, Hana Manceau, Anvi Laetitia Nguyen, Boualem Moulouel, Nathalie Dessendier, Neila Talbi, Hervé Puy, Christophe Junot, Laurent Gouya, Caroline Schmitt, Thibaud Lefebvre
Background The quantification of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) in urine are the first-line tests for diagnosis and monitoring of acute hepatic porphyrias (AHP). Ion-exchange chromatography (IEC), which is time- and staff-consuming and limited to urine, is still the preferred method in many specialized laboratories, despite the development of mass spectrometry-based methods
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Specific Cryptosporidium antigens associate with reinfection immunity and protection from cryptosporidiosis J. Clin. Invest. (IF 15.9) Pub Date : 2023 Carol A. Gilchrist, Joseph J. Campo, Jozelyn V. Pablo, Jennie Z. Ma, Andy Teng, Amit Oberai, Adam D. Shandling, Masud Alam, Mamun Kabir, A.S.G. Faruque, Rashidul Haque, William A. Petri Jr.
There is no vaccine to protect from cryptosporidiosis, a leading cause of diarrhea in infants in low- and middle-income countries. Here, we comprehensively identified parasite antigens associated with protection from reinfection. A Cryptosporidium protein microarray was constructed by in vitro transcription and translation of 1,761 C. parvum, C. hominis, or C. meleagridis antigens, including proteins
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Molecular correlates of vaccine-induced protection against typhoid fever J. Clin. Invest. (IF 15.9) Pub Date : 2023 Henderson Zhu, Irina Chelysheva, Deborah L. Cross, Luke Blackwell, Celina Jin, Malick M. Gibani, Elizabeth Jones, Jennifer Hill, Johannes Trück, Dominic F. Kelly, Christoph J. Blohmke, Andrew J. Pollard, Daniel O’Connor
BACKGROUND. Typhoid fever is caused by the Gram-negative bacterium Salmonella enterica serovar Typhi and poses a substantial public health burden worldwide. Vaccines have been developed based on the surface Vi-capsular polysaccharide of S. Typhi; these include a plain-polysaccharide-based vaccine, ViPS, and a glycoconjugate vaccine, ViTT. To understand immune responses to these vaccines and their vaccine-induced
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A phase II study of Bruton’s tyrosine kinase inhibition for the prevention of anaphylaxis J. Clin. Invest. (IF 15.9) Pub Date : 2023 Ragha V. Suresh, Collin Dunnam, Dhananjay Vaidya, Robert A. Wood, Bruce S. Bochner, Donald W. MacGlashan Jr., Melanie C. Dispenza
BACKGROUND. IgE-mediated anaphylaxis is a potentially fatal systemic allergic reaction for which there are no currently FDA-approved preventative therapies. Bruton’s tyrosine kinase (BTK) is an essential enzyme for IgE-mediated signaling pathways and is an ideal pharmacologic target to prevent allergic reactions. In this open-label trial, we evaluated the safety and efficacy of acalabrutinib, a BTK
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Active transcription in the vascular bed characterizes rapid progression in idiopathic pulmonary fibrosis J. Clin. Invest. (IF 15.9) Pub Date : 2023 Nirmal S. Sharma, Kapil Patel, Ezgi Sari, Shruti Shankar, Maria G. Gastanadui, Diego Moncada-Giraldo, Yixel Soto-Vazquez, Delores Stacks, Louise Hecker, Kevin Dsouza, Mudassir Banday, Edward O’Neill, Paul Benson, Gregory Payne, Camilla Margaroli, Amit Gaggar
To the Editor: Idiopathic pulmonary fibrosis (IPF) is the most common manifestation of interstitial lung disease, with a median survival of 3–5 years after diagnosis. IPF is characterized by progressive fibrosis with the development of fibroblastic foci in the interstitium. Despite the short median survival, there is a striking variance in the clinical course of IPF, with some patients characterized
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Cotargeting a MYC/eIF4A-survival axis improves the efficacy of KRAS inhibitors in lung cancer J. Clin. Invest. (IF 15.9) Pub Date : 2023 Francesca Nardi, Naiara Perurena, Amy E. Schade, Ze-Hua Li, Kenneth Ngo, Elena V. Ivanova, Aisha Saldanha, Chendi Li, Prafulla C. Gokhale, Aaron N. Hata, David A. Barbie, Cloud P. Paweletz, Pasi A. Jänne, Karen Cichowski
Despite the success of KRAS G12C inhibitors in non–small cell lung cancer (NSCLC), more effective treatments are needed. One preclinical strategy has been to cotarget RAS and mTOR pathways; however, toxicity due to broad mTOR inhibition has limited its utility. Therefore, we sought to develop a more refined means of targeting cap-dependent translation and identifying the most therapeutically important
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Long-acting lenacapavir acts as an effective preexposure prophylaxis in a rectal SHIV challenge macaque model J. Clin. Invest. (IF 15.9) Pub Date : 2023 Elena Bekerman, Stephen R. Yant, Laurie VanderVeen, Derek Hansen, Bing Lu, William Rowe, Kelly Wang, Christian Callebaut
Long-acting antiretroviral agents for preexposure prophylaxis (PrEP) represent a promising new alternative to daily oral regimens for HIV prevention. Lenacapavir (LEN) is a first-in-class long-acting capsid inhibitor approved for the treatment of HIV-1 infection. Here, we assessed the efficacy of LEN for PrEP using a single high-dose simian-human immunodeficiency virus (SHIV) rectal challenge macaque
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Transepidermal water loss rises before food anaphylaxis and predicts food challenge outcomes J. Clin. Invest. (IF 15.9) Pub Date : 2023 Charles F. Schuler IV, Kelly M. O’Shea, Jonathan P. Troost, Bridgette Kaul, Christopher M. Launius, Jayme Cannon, David M. Manthei, George E. Freigeh, Georgiana M. Sanders, Simon P. Hogan, Nicholas W. Lukacs, James R. Baker Jr.
BACKGROUND. Food allergy (FA) is a growing health problem requiring physiologic confirmation via the oral food challenge (OFC). Many OFCs result in clinical anaphylaxis, causing discomfort and risk while limiting OFC utility. Transepidermal water loss (TEWL) measurement provides a potential solution to detect food anaphylaxis in real time prior to clinical symptoms. We evaluated whether TEWL changes
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Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43–related neurodegeneration J. Clin. Invest. (IF 15.9) Pub Date : 2023 Leon Tejwani, Youngseob Jung, Hiroshi Kokubu, Sowmithra Sowmithra, Luhan Ni, Changwoo Lee, Benjamin Sanders, Paul J. Lee, Yangfei Xiang, Kimberly Luttik, Armand Soriano, Jennifer Yoon, Junhyun Park, Hannah H. Ro, Hyoungseok Ju, Clara Liao, Sofia Massaro Tieze, Frank Rigo, Paymaan Jafar-Nejad, Janghoo Lim
Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP, encoding transactive response DNA-binding protein 43 kDa (TDP-43), account for less than 1% of all ALS cases, TDP-43–positive aggregates are present in nearly all ALS patients, including patients with sporadic ALS (sALS) or carrying other familial ALS–causing
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SCCA1/SERPINB3 suppresses antitumor immunity and blunts therapy-induced T cell responses via STAT-dependent chemokine production J. Clin. Invest. (IF 15.9) Pub Date : 2023 Liyun Chen, Victoria Shi, Songyan Wang, Lulu Sun, Rebecca Freeman, Jasmine Yang, Matthew J. Inkman, Subhajit Ghosh, Fiona Ruiz, Kay Jayachandran, Yi Huang, Jingqin Luo, Jin Zhang, Pippa Cosper, Clifford J. Luke, Catherine S. Spina, Perry W. Grigsby, Julie K. Schwarz, Stephanie Markovina
Patients with cancer who have high serum levels of squamous cell carcinoma antigen 1 (SCCA1, now referred to as SERPINB3) commonly experience treatment resistance and have a poor prognosis. Despite being a clinical biomarker, the modulation of SERPINB3 in tumor immunity is poorly understood. We found positive correlations of SERPINB3 with CXCL1, CXCL8 (CXCL8/9), S100A8, and S100A9 (S100A8/A9) myeloid
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Ruxolitinib improves hematopoietic regeneration by restoring mesenchymal stromal cell function in acute graft-versus-host disease J. Clin. Invest. (IF 15.9) Pub Date : 2023 Yan Lin, Quan Gu, Shihong Lu, Zengkai Pan, Zining Yang, Yapu Li, Shangda Yang, Yanling Lv, Zhaofeng Zheng, Guohuan Sun, Fanglin Gou, Chang Xu, Xiangnan Zhao, Fengjiao Wang, Chenchen Wang, Shiru Yuan, Xiaobao Xie, Yang Cao, Yue Liu, Weiying Gu, Tao Cheng, Hui Cheng, Xiaoxia Hu
Acute graft-versus-host disease (aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. Hematopoietic dysfunction accompanied by severe aGVHD, which may be caused by niche impairment, is a long-standing clinical problem. However, how the bone marrow (BM) niche is damaged in aGVHD hosts is poorly defined. To comprehensively address this question, we used a haplo-MHC–matched
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Phospholipid scramblase-1 regulates innate type 2 inflammation in mouse lungs via CRTH2-dependent mechanisms J. Clin. Invest. (IF 15.9) Pub Date : 2023 Ashley Hernandez-Gutierrez, Sonoor Majid, Adam Eberle, Ashley Choi, Parand Sorkhdini, Dongqin Yang, Alina Xiaoyu Yang, Carmelissa Norbrun, Chuan Hua He, Chang-min Lee, Chun Geun Lee, Jack A. Elias, Yang Zhou
Exaggerated Type 2 immune responses play critical roles in the pathogenesis of a variety of diseases including asthma, allergy, and pulmonary fibrosis. Recent studies have highlighted the importance of innate type 2 immune responses and innate lymphoid 2 cells (ILC2s) in these disorders. However, the mechanisms that control the development of pulmonary innate type 2 responses (IT2IR) and the recruitment
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Macrophage–endothelial cell crosstalk orchestrates neutrophil recruitment in inflamed mucosa J. Clin. Invest. (IF 15.9) Pub Date : 2023 Xingsheng Ren, Laura D. Manzanares, Enzo B. Piccolo, Jessica M. Urbanczyk, David P. Sullivan, Lenore K. Yalom, Triet M. Bui, Connor Lantz, Hinda Najem, Parambir S. Dulai, Amy B. Heimberger, Edward B. Thorp, Ronen Sumagin
Neutrophil (PMN) mobilization to sites of insult is critical for host defense and requires transendothelial migration (TEM). TEM involves several well-studied sequential adhesive interactions with vascular endothelial cells (ECs); however, what initiates or terminates this process is not well-understood. Here, we describe what we believe to be a new mechanism where vessel-associated macrophages through
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Pancreatic regional blood flow links the endocrine and exocrine diseases J. Clin. Invest. (IF 15.9) Pub Date : 2023 Adam A. Rizk, Michael P. Dybala, Khalil C. Rodriguez, Marjan Slak Rupnik, Manami Hara
An increasing number of studies have demonstrated that disease states of the endocrine or exocrine pancreas aggravate one another, which implies bidirectional blood flow between islets and exocrine cells. However, this is inconsistent with the current model of unidirectional blood flow, which is strictly from islets to exocrine tissues. This conventional model was first proposed in 1932, and it has
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Monocyte-derived macrophages orchestrate multiple cell-type interactions to repair necrotic liver lesions in disease models J. Clin. Invest. (IF 15.9) Pub Date : 2023 Dechun Feng, Xiaogang Xiang, Yukun Guan, Adrien Guillot, Hongkun Lu, Chingwen Chang, Yong He, Hua Wang, Hongna Pan, Cynthia Ju, Sean P. Colgan, Frank Tacke, Xin Wei Wang, George Kunos, Bin Gao
The liver can fully regenerate after partial resection, and its underlying mechanisms have been extensively studied. The liver can also rapidly regenerate after injury, with most studies focusing on hepatocyte proliferation; however, how hepatic necrotic lesions during acute or chronic liver diseases are eliminated and repaired remains obscure. Here, we demonstrate that monocyte-derived macrophages
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Chemokine receptor CXCR7 activates Aurora Kinase A and promotes neuroendocrine prostate cancer growth J. Clin. Invest. (IF 15.9) Pub Date : 2023 Galina Gritsina, Ka-wing Fong, Xiaodong Lu, Zhuoyuan Lin, Wanqing Xie, Shivani Agarwal, Dong Lin, Gary E. Schiltz, Himisha Beltran, Eva Corey, Colm Morrissey, Yuzhuo Wang, Jonathan C. Zhao, Maha Hussain, Jindan Yu
CXCR7 is an atypical chemokine receptor that recruits β-arrestin (ARRB2) and internalizes into clathrin-coated intracellular vesicles where the complex acts as a scaffold for cytoplasmic kinase assembly and signal transduction. Here, we report that CXCR7 was elevated in the majority of prostate cancer (PCa) cases with neuroendocrine features (NEPC). CXCR7 markedly induced mitotic spindle and cell cycle
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Hypertriglyceridemia-Associated Pancreatitis: New Concepts and Potential Mechanisms Clin. Chem. (IF 9.3) Pub Date : 2023-08-02 Signe E J Hansen, Anette Varbo, Børge G Nordestgaard, Anne Langsted
Background Triglycerides are a major source of energy, while high plasma triglycerides are a risk factor for various diseases and premature death. Severely elevated plasma triglycerides are a well-established cause of acute pancreatitis with high mortality, likely due to the presence of elevated levels of chylomicrons and large very low-density lipoproteins in plasma. As markedly elevated levels of
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Reference Interval Harmonization: Harnessing the Power of Big Data Analytics to Derive Common Reference Intervals across Populations and Testing Platforms Clin. Chem. (IF 9.3) Pub Date : 2023-07-21 Mary Kathryn Bohn, Dana Bailey, Cynthia Balion, George Cembrowski, Christine Collier, Vincent De Guire, Victoria Higgins, Benjamin Jung, Zahraa Mohammed Ali, David Seccombe, Jennifer Taher, Albert K Y Tsui, Allison Venner, Khosrow Adeli
Background Harmonization in laboratory medicine is essential for consistent and accurate clinical decision-making. There is significant and unwarranted variation in reference intervals (RIs) used by laboratories for assays with established analytical traceability. The Canadian Society of Clinical Chemists (CSCC) Working Group on Reference Interval Harmonization (hRI-WG) aims to establish harmonized
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Urinary Kidney Injury Biomarkers Are Associated with Ischemia-Reperfusion Injury Severity in Kidney Allograft Recipients Clin. Chem. (IF 9.3) Pub Date : 2023-07-21 Tirsa T van Duijl, Esther N M de Rooij, Maxim M Treep, Marte E Koelemaij, Fred P H T M Romijn, Ellen K Hoogeveen, L Renee Ruhaak, Saskia le Cessie, Johan W de Fijter, Christa M Cobbaert
Background We explored the potential of emerging and conventional urinary kidney injury biomarkers in recipients of living donor (LD) or donation after circulatory death (DCD) kidney transplantation, patients with chronic kidney disease (CKD), and individuals from the general population. Methods Urine samples from kidney allograft recipients with mild (LD; n = 199) or severe (DCD; n = 71) ischemia-reperfusion
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Body Composition Measures and N-terminal pro-B-type Natriuretic Peptide (NT-pro-BNP) in US Adults Clin. Chem. (IF 9.3) Pub Date : 2023-07-21 Justin B Echouffo-Tcheugui, Sui Zhang, John W McEvoy, Stephen P Juraschek, Josef Coresh, Robert H Christenson, Chiadi E Ndumele, Elizabeth Selvin
Background The associations of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) with dual energy x-ray absorptiometry (DEXA)-derived measures of body mass and composition are largely unknown. Methods We included participants aged ≥20 years from the 1999–2004 National Health and Nutrition Examination Survey with NT-pro-BNP and DEXA-derived body composition (fat and lean mass) measures. We used
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Circulating Cell-Free SEPT9 DNA Methylation in Blood Is a Biomarker for Minimal Residual Disease Detection in Head and Neck Squamous Cell Carcinoma Patients Clin. Chem. (IF 9.3) Pub Date : 2023-07-21 Dimo Dietrich, Simone Weider, Luka de Vos, Timo Jakob Vogt, Moritz Färber, Romina Zarbl, Alina Hunecke, Ann-Kathrin Glosch, Jennis Gabrielpillai, Friedrich Bootz, Franz-Georg Bauernfeind, Franz-Josef Kramer, Glen Kristiansen, Peter Brossart, Sebastian Strieth, Alina Franzen
Background Tumorous SEPT9 (septin 9, SEPTIN9) circulating cell-free DNA (ccfDNA) methylation in blood plasma is a powerful biomarker for diagnosis, molecular staging, prognosis, and recurrence monitoring in head and neck squamous cell carcinoma (HNSCC) patients. The present study aimed to evaluate the clinical performance of SEPT9 ccfDNA methylation to detect post-surgical minimal residual disease
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Third-Generation Single-Molecule Sequencing for Preimplantation Genetic Testing of Aneuploidy and Segmental Imbalances Clin. Chem. (IF 9.3) Pub Date : 2023-07-21 Vivienne J Tan, Timing Liu, Zainul Arifin, Beatrice Pak, Arnold S C Tan, Simin Wong, Chiea-Chuen Khor, Henry Yang, Caroline G Lee, Zhongwei Huang, Mahesh A Choolani, Samuel S Chong
Background Current strategies for preimplantation genetic testing for aneuploidy or structural rearrangements (PGT-A/SR) rely mainly on next-generation sequencing (NGS) and microarray platforms, which are robust but require expensive instrumentation. We explored the suitability of third-generation single-molecule sequencing as a PGT-A/SR screening platform for both aneuploidy and segmental imbalance
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APOE-ε4 synergizes with sleep disruption to accelerate Aβ deposition and Aβ-associated tau seeding and spreading J. Clin. Invest. (IF 15.9) Pub Date : 2023 Chanung Wang, Aishwarya Nambiar, Michael R. Strickland, Choonghee Lee, Samira Parhizkar, Alec C. Moore, Erik S. Musiek, Jason D. Ulrich, David M. Holtzman
Alzheimer’s disease (AD) is the most common cause of dementia. The APOE-ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD. The APOE genotype modulates the effect of sleep disruption on AD risk, suggesting a possible link between apoE and sleep in AD pathogenesis, which is relatively unexplored. We hypothesized that apoE modifies Aβ deposition and Aβ
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Human endogenous retrovirus onco-exaptation counters cancer cell senescence through calbindin J. Clin. Invest. (IF 15.9) Pub Date : 2023 Jan Attig, Judith Pape, Laura Doglio, Anastasiya Kazachenka, Eleonora Ottina, George R. Young, Katey S.S. Enfield, Iker Valle Aramburu, Kevin W. Ng, Nikhil Faulkner, William Bolland, Venizelos Papayannopoulos, Charles Swanton, George Kassiotis
Increased levels and diversity of human endogenous retrovirus (HERV) transcription characterize most cancer types and are linked with disease outcomes. However, the underlying processes are incompletely understood. Here, we show that elevated transcription of HERVH proviruses predicted survival of lung squamous cell carcinoma (LUSC) and identified an isoform of CALB1, encoding calbindin, ectopically
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1-Deoxynojirimycin promotes cardiac function and rescues mitochondrial cristae in mitochondrial hypertrophic cardiomyopathy J. Clin. Invest. (IF 15.9) Pub Date : 2023 Qianqian Zhuang, Fengfeng Guo, Lei Fu, Yufei Dong, Shaofang Xie, Xue Ding, Shuangyi Hu, Xuanhao D. Zhou, Yangwei Jiang, Hui Zhou, Yue Qiu, Zhaoying Lei, Mengyao Li, Huajian Cai, Mingjie Fan, Lingjie Sang, Yong Fu, Dong Zhang, Aifu Lin, Xu Li, Tilo Kunath, Ruhong Zhou, Ping Liang, Zhong Liu, Qingfeng Yan
Hypertrophic cardiomyopathy (HCM) is the most prominent cause of sudden cardiac death in young people. Due to heterogeneity in clinical manifestations, conventional HCM drugs have limitations for mitochondrial hypertrophic cardiomyopathy. Discovering more effective compounds would be of substantial benefit for further elucidating the pathogenic mechanisms of HCM and treating patients with this condition
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Anoctamin 4 channel currents activate glucose-inhibited neurons in the mouse ventromedial hypothalamus during hypoglycemia J. Clin. Invest. (IF 15.9) Pub Date : 2023 Longlong Tu, Jonathan C. Bean, Yang He, Hailan Liu, Meng Yu, Hesong Liu, Nan Zhang, Na Yin, Junying Han, Nikolas A. Scarcelli, Kristine M. Conde, Mengjie Wang, Yongxiang Li, Bing Feng, Peiyu Gao, Zhao-Lin Cai, Makoto Fukuda, Mingshan Xue, Qingchun Tong, Yongjie Yang, Lan Liao, Jianming Xu, Chunmei Wang, Yanlin He, Yong Xu
Glucose is the basic fuel essential for maintenance of viability and functionality of all cells. However, some neurons — namely, glucose-inhibited (GI) neurons — paradoxically increase their firing activity in low-glucose conditions and decrease that activity in high-glucose conditions. The ionic mechanisms mediating electric responses of GI neurons to glucose fluctuations remain unclear. Here, we
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Anti–miR-93-5p therapy prolongs sepsis survival by restoring the peripheral immune response J. Clin. Invest. (IF 15.9) Pub Date : 2023 Mihnea P. Dragomir, Enrique Fuentes-Mattei, Melanie Winkle, Keishi Okubo, Recep Bayraktar, Erik Knutsen, Aiham Qdaisat, Meng Chen, Yongfeng Li, Masayoshi Shimizu, Lan Pang, Kevin Liu, Xiuping Liu, Simone Anfossi, Huanyu Zhang, Ines Koch, Anh M. Tran, Swati Mohapatra, Anh Ton, Mecit Kaplan, Matthew W. Anderson, Spencer J. Rothfuss, Robert Silasi, Ravi S. Keshari, Manuela Ferracin, Cristina Ivan, Cristian
Sepsis remains a leading cause of death for humans and currently has no pathogenesis-specific therapy. Hampered progress is partly due to a lack of insight into deep mechanistic processes. In the past decade, deciphering the functions of small noncoding miRNAs in sepsis pathogenesis became a dynamic research topic. To screen for new miRNA targets for sepsis therapeutics, we used samples for miRNA array
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International Perspectives on GFR Estimation and Race-Based Adjustments. Clin. Chem. (IF 9.3) Pub Date : 2023-07-15 Joe M El-Khoury,Amy B Karger,Etienne Cavalier,Robert Kalyesubula,Boon Wee Teo,Verônica T Costa E Silva,Lesley A Inker
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Feasibility of Targeted Next-Generation DNA Sequencing for Expanding Population Newborn Screening Clin. Chem. (IF 9.3) Pub Date : 2023-07-14 Bennett Oh Vic Shum, Carel Jacobus Pretorius, Letitia Min Fen Sng, Ilya Henner, Paulette Barahona, Emre Basar, Jim McGill, Urs Wilgen, Anna Zournazi, Lilian Downie, Natalie Taylor, Liam Cheney, Sylvania Wu, Natalie Angela Twine, Denis Carolin Bauer, Gerald Francis Watts, Akash Navilebasappa, Kishore Rajagopal Kumar, Jacobus Petrus Johannes Ungerer, Glenn Bennett
Background Newborn screening (NBS) is an effective public health intervention that reduces death and disability from treatable genetic diseases, but many conditions are not screened due to a lack of a suitable assay. Whole genome and whole exome sequencing can potentially expand NBS but there remain many technical challenges preventing their use in population NBS. We investigated if targeted gene sequencing
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Increasing Confidence in a Phosphatidylethanol 16:0/18:1 Cutoff at 20 ng/mL to Support Abstinence or Minor Intake of Alcohol. Clin. Chem. (IF 9.3) Pub Date : 2023-07-10 Katleen Van Uytfanghe,Christophe P Stove
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Reference Interval Harmonization: Will Big Data Provide a Solution? Clin. Chem. (IF 9.3) Pub Date : 2023-07-10 Ferruccio Ceriotti,Matteo Vidali
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Commentary on Abnormal Hb A1c Result from a Diabetic Patient Leads to Unexpected Diagnosis. Clin. Chem. (IF 9.3) Pub Date : 2023-07-05 Timothy J McDonald
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Plasma Is Denser than Cells and Gel Barrier. Is It Possible? Clin. Chem. (IF 9.3) Pub Date : 2023-07-05 Jayson V Pagaduan,Ghaith Altawallbeh
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The Ethical Dilemma of a Patient's Immediate Access to Test Results. Clin. Chem. (IF 9.3) Pub Date : 2023-07-05 Stephanie A Hart,Joesph R Wiencek
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Abnormal Hb A1c Result from a Diabetic Patient Leads to Unexpected Diagnosis. Clin. Chem. (IF 9.3) Pub Date : 2023-07-05 Nicole J Mathewson,Lauren N Pearson,Kelly Doyle
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Commentary on Abnormal Hb A1c Result from a Diabetic Patient Leads to Unexpected Diagnosis. Clin. Chem. (IF 9.3) Pub Date : 2023-07-05 Randie R Little
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Targeting hypoxia-inducible factors with 32-134D safely and effectively treats diabetic eye disease in mice J. Clin. Invest. (IF 15.9) Pub Date : 2023 Jing Zhang, Deepti Sharma, Aumreetam Dinabandhu, Jaron Sanchez, Brooks Applewhite, Kathleen Jee, Monika Deshpande, Miguel Flores-Bellver, Ming-Wen Hu, Chuanyu Guo, Shaima Salman, Yousang Hwang, Nicole M. Anders, Michelle A. Rudek, Jiang Qian, M. Valeria Canto-Soler, Gregg L. Semenza, Silvia Montaner, Akrit Sodhi
Many patients with diabetic eye disease respond inadequately to anti-VEGF therapies, implicating additional vasoactive mediators in its pathogenesis. We demonstrate that levels of angiogenic proteins regulated by HIF-1 and -2 remain elevated in the eyes of people with diabetes despite treatment with anti-VEGF therapy. Conversely, by inhibiting HIFs, we normalized the expression of multiple vasoactive
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Human endogenous retrovirus K contributes to a stem cell niche in glioblastoma J. Clin. Invest. (IF 15.9) Pub Date : 2023 Ashish H. Shah, Sarah R. Rivas, Tara T. Doucet-O’Hare, Vaidya Govindarajan, Catherine DeMarino, Tongguang Wang, Leonel Ampie, Yong Zhang, Yeshavanth Kumar Banasavadi-Siddegowda, Stuart Walbridge, Dragan Maric, Marta Garcia-Montojo, Robert K. Suter, Myoung-Hwa Lee, Kareem A. Zaghloul, Joseph Steiner, Abdel G. Elkahloun, Jay Chandar, Deepa Seetharam, Jelisah Desgraves, Wenxue Li, Kory Johnson, Michael
Human endogenous retroviruses (HERVs) are ancestral viral relics that constitute nearly 8% of the human genome. Although normally silenced, the most recently integrated provirus HERV-K (HML-2) can be reactivated in certain cancers. Here, we report pathological expression of HML-2 in malignant gliomas in both cerebrospinal fluid and tumor tissue that was associated with a cancer stem cell phenotype
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The SWI/SNF chromatin-remodeling subunit DPF2 facilitates NRF2-dependent antiinflammatory and antioxidant gene expression J. Clin. Invest. (IF 15.9) Pub Date : 2023 Gloria Mas, Na Man, Yuichiro Nakata, Concepcion Martinez-Caja, Daniel Karl, Felipe Beckedorff, Francesco Tamiro, Chuan Chen, Stephanie Duffort, Hidehiro Itonaga, Adnan K. Mookhtiar, Kranthi Kunkalla, Alfredo M. Valencia, Clayton K. Collings, Cigall Kadoch, Francisco Vega, Scott C. Kogan, Lluis Morey, Daniel Bilbao, Stephen D. Nimer
During emergency hematopoiesis, hematopoietic stem cells (HSCs) rapidly proliferate to produce myeloid and lymphoid effector cells, a response that is critical against infection or tissue injury. If unresolved, this process leads to sustained inflammation, which can cause life-threatening diseases and cancer. Here, we identify a role of double PHD fingers 2 (DPF2) in modulating inflammation. DPF2 is
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Atrx deletion impairs CGAS/STING signaling and increases sarcoma response to radiation and oncolytic herpesvirus J. Clin. Invest. (IF 15.9) Pub Date : 2023 Warren Floyd, Matthew Pierpoint, Chang Su, Rutulkumar Patel, Lixia Luo, Katherine Deland, Amy J. Wisdom, Daniel Zhu, Yan Ma, Suzanne Bartholf DeWitt, Nerissa T. Williams, Alexander L. Lazarides, Jason A. Somarelli, David L. Corcoran, William C. Eward, Diana M. Cardona, David G. Kirsch
ATRX is one of the most frequently altered genes in solid tumors, and mutation is especially frequent in soft tissue sarcomas. However, the role of ATRX in tumor development and response to cancer therapies remains poorly understood. Here, we developed a primary mouse model of soft tissue sarcoma and showed that Atrx-deleted tumors were more sensitive to radiation therapy and to oncolytic herpesvirus
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CDK4-E2F3 signals enhance oxidative skeletal muscle fiber numbers and function to affect myogenesis and metabolism J. Clin. Invest. (IF 15.9) Pub Date : 2023 Young Jae Bahn, Hariom Yadav, Paolo Piaggi, Brent S. Abel, Oksana Gavrilova, Danielle A. Springer, Ioannis Papazoglou, Patricia M. Zerfas, Monica C. Skarulis, Alexandra C. McPherron, Sushil G. Rane
Understanding how skeletal muscle fiber proportions are regulated is vital to understanding muscle function. Oxidative and glycolytic skeletal muscle fibers differ in their contractile ability, mitochondrial activity, and metabolic properties. Fiber-type proportions vary in normal physiology and disease states, although the underlying mechanisms are unclear. In human skeletal muscle, we observed that
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PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis J. Clin. Invest. (IF 15.9) Pub Date : 2023 Kallesh D. Jayappa, Brian Tran, Vicki L. Gordon, Christopher Morris, Shekhar Saha, Caroline C. Farrington, Caitlin M. O’Connor, Kaitlin P. Zawacki, Krista M. Isaac, Mark Kester, Timothy P. Bender, Michael E. Williams, Craig A. Portell, Michael J. Weber, Goutham Narla
Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple antiapoptotic proteins and display resistance to proapoptotic agents. Here, we demonstrated that multidrug-resistant CLL cells in vivo exhibited apoptosis restriction at a pre-mitochondrial
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Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma J. Clin. Invest. (IF 15.9) Pub Date : 2023 Benedetta Apollonio, Filomena Spada, Nedyalko Petrov, Domenico Cozzetto, Despoina Papazoglou, Peter Jarvis, Shichina Kannambath, Manuela Terranova-Barberio, Rose-Marie Amini, Gunilla Enblad, Charlotte Graham, Reuben Benjamin, Elisabeth Phillips, Richard Ellis, Rosamond Nuamah, Mansoor Saqi, Dinis P. Calado, Richard Rosenquist, Lesley A. Sutton, Jon Salisbury, Georgios Zacharioudakis, Anna Vardi, Patrick
Recent transcriptomic-based analysis of diffuse large B cell lymphoma (DLBCL) has highlighted the clinical relevance of LN fibroblast and tumor-infiltrating lymphocyte (TIL) signatures within the tumor microenvironment (TME). However, the immunomodulatory role of fibroblasts in lymphoma remains unclear. Here, by studying human and mouse DLBCL-LNs, we identified the presence of an aberrantly remodeled
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Prevalence and functional profile of SARS-CoV-2 T cells in asymptomatic Kenyan adults J. Clin. Invest. (IF 15.9) Pub Date : 2023 Taraz Samandari, Joshua B. Ongalo, Kimberly D. McCarthy, Richard K. Biegon, Philister A. Madiega, Anne Mithika, Joseph Orinda, Grace M. Mboya, Patrick Mwaura, Omu Anzala, Clayton Onyango, Fredrick O. Oluoch, Eric Osoro, Charles-Antoine Dutertre, Nicole Tan, Shou Kit Hang, Smrithi Hariharaputran, David C. Lye, Amy Herman-Roloff, Nina Le Bert, Antonio Bertoletti
Background. SARS-CoV-2 infection in Africa has been characterized by a less severe disease profile than what has been observed elsewhere, but the profile of SARS-CoV-2–specific adaptive immunity in these mainly asymptomatic patients has not, to our knowledge, been analyzed.
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T-BET and EOMES sustain mature human NK cell identity and antitumor function J. Clin. Invest. (IF 15.9) Pub Date : 2023 Pamela Wong, Jennifer A. Foltz, Lily Chang, Carly C. Neal, Tony Yao, Celia C. Cubitt, Jennifer Tran, Samantha Kersting-Schadek, Sathvik Palakurty, Natalia Jaeger, David A. Russler-Germain, Nancy D. Marin, Margery Gang, Julia A. Wagner, Alice Y. Zhou, Miriam T. Jacobs, Mark Foster, Timothy Schappe, Lynne Marsala, Ethan McClain, Patrick Pence, Michelle Becker-Hapak, Bryan Fisk, Allegra A. Petti, Obi
Since the T-box transcription factors (TFs) T-BET and EOMES are necessary for initiation of NK cell development, their ongoing requirement for mature NK cell homeostasis, function, and molecular programming remains unclear. To address this, T-BET and EOMES were deleted in unexpanded primary human NK cells using CRISPR/Cas9. Deleting these TFs compromised in vivo antitumor response of human NK cells
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The potential role of human endogenous retrovirus K in glioblastoma J. Clin. Invest. (IF 15.9) Pub Date : 2023 Parvinder Hothi, Charles Cobbs
The most active human endogenous retrovirus K (HERV-K) subtype, HML-2, has been implicated as a driver of oncogenesis in several cancers. However, the presence and function of HML-2 in malignant gliomas has remained unclear. In this issue of the JCI, Shah and colleagues demonstrate HML-2 overexpression in glioblastoma (GBM) and its role in maintaining the cancer stem cell phenotype. Given that stem-like
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The selenoprotein P–LRP5/6–WNT3A complex promotes tumorigenesis in sporadic colorectal cancer J. Clin. Invest. (IF 15.9) Pub Date : 2023 K. Sandeep Prabhu
Some studies suggest that the trace element selenium protects against colorectal cancer (CRC). However, the contribution of selenoprotein P (SELENOP), a unique selenocysteine-containing protein, to sporadic colorectal carcinogenesis challenges this paradigm. SELENOP is predominately secreted by the liver but is also expressed in various cells of the small intestine and colon in mice and humans. In
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Host genetic background is a barrier to broadly effective vaccine–mediated protection against tuberculosis J. Clin. Invest. (IF 15.9) Pub Date : 2023 Rocky Lai, Diana N. Gong, Travis Williams, Abiola F. Ogunsola, Kelly Cavallo, Cecilia S. Lindestam Arlehamn, Sarah Acolatse, Gillian L. Beamer, Martin T. Ferris, Christopher M. Sassetti, Douglas A. Lauffenburger, Samuel M. Behar
Heterogeneity in human immune responses is difficult to model in standard laboratory mice. To understand how host variation affects Bacillus Calmette Guerin–induced (BCG-induced) immunity against Mycobacterium tuberculosis, we studied 24 unique collaborative cross (CC) mouse strains, which differ primarily in the genes and alleles they inherit from founder strains. The CC strains were vaccinated with
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Identification and validation of urinary CXCL9 as a biomarker for diagnosis of acute interstitial nephritis J. Clin. Invest. (IF 15.9) Pub Date : 2023 Dennis G. Moledina, Wassim Obeid, Rex N. Smith, Ivy Rosales, Meghan E. Sise, Gilbert Moeckel, Michael Kashgarian, Michael Kuperman, Kirk N. Campbell, Sean Lefferts, Kristin Meliambro, Markus Bitzer, Mark A. Perazella, Randy L. Luciano, Jordan S. Pober, Lloyd G. Cantley, Robert B. Colvin, F. Perry Wilson, Chirag R. Parikh
Background. Acute tubulointerstitial nephritis (AIN) is one of the few causes of acute kidney injury with diagnosis-specific treatment options. However, due to the need to obtain a kidney biopsy for histological confirmation, AIN diagnosis can be delayed, missed, or incorrectly assumed. Here, we identify and validate urinary CXCL9, an IFN-γ-induced chemokine involved in lymphocyte chemotaxis, as a
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iPSC-derived reactive astrocytes from patients with multiple sclerosis protect cocultured neurons in inflammatory conditions J. Clin. Invest. (IF 15.9) Pub Date : 2023 Janis Kerkering, Bakhrom Muinjonov, Kamil S. Rosiewicz, Sebastian Diecke, Charlotte Biese, Juliane Schiweck, Claudia Chien, Dario Zocholl, Thomas Conrad, Friedemann Paul, Marlen Alisch, Volker Siffrin
Multiple sclerosis (MS) is the most common chronic central nervous system inflammatory disease. Individual courses are highly variable, with complete remission in some patients and relentless progression in others. We generated induced pluripotent stem cells (iPSCs) to investigate possible mechanisms in benign MS (BMS), compared with progressive MS (PMS). We differentiated neurons and astrocytes that
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Biomarkers in acute kidney injury: On the cusp of a new era? J. Clin. Invest. (IF 15.9) Pub Date : 2023 Mark Canney, Edward G. Clark, Swapnil Hiremath
The field of nephrology has been slow in moving beyond the utilization of creatinine as an indicator for chronic kidney disease and acute kidney injury (AKI). Early diagnosis and establishment of etiology, in particular, are important for treatment of AKI. In the setting of hospital-acquired AKI, tubular injury is more common, but acute interstitial nephritis (AIN) has a more treatable etiology. However
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Discovering the fibroblastic reticular cell in the immune tumor microenvironment in lymphoma J. Clin. Invest. (IF 15.9) Pub Date : 2023 Adam Yuh Lin, Leo I. Gordon
The study of the cellular and molecular microenvironment in B cell lymphoma, especially diffuse large B cell lymphoma (DLBCL), has led to prognostic and therapeutic algorithms that may improve patient outcomes. Emerging gene signature panels provide a granular understanding of DLBCL based on the immune tumor microenvironment (iTME). In addition, some gene signatures identify lymphomas that are more
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Net39 protects muscle nuclei from mechanical stress during the pathogenesis of Emery-Dreifuss muscular dystrophy J. Clin. Invest. (IF 15.9) Pub Date : 2023 Yichi Zhang, Andres Ramirez-Martinez, Kenian Chen, John R. McAnally, Chunyu Cai, Mateusz Z. Durbacz, Francesco Chemello, Zhaoning Wang, Lin Xu, Rhonda Bassel-Duby, Ning Liu, Eric N. Olson
Mutations in genes encoding nuclear envelope proteins lead to diseases known as nuclear envelopathies, characterized by skeletal muscle and heart abnormalities, such as Emery-Dreifuss muscular dystrophy (EDMD). The tissue-specific role of the nuclear envelope in the etiology of these diseases has not been extensively explored. We previously showed that global deletion of the muscle-specific nuclear
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Disrupting pathologic phase transitions in neurodegeneration J. Clin. Invest. (IF 15.9) Pub Date : 2023 Bryan T. Hurtle, Longxin Xie, Christopher J. Donnelly
Solid-like protein deposits found in aged and diseased human brains have revealed a relationship between insoluble protein accumulations and the resulting deficits in neurologic function. Clinically diverse neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis, exhibit unique and disease-specific biochemical
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SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactions J. Clin. Invest. (IF 15.9) Pub Date : 2023 Jennifer M. Pilat, Rachel E. Brown, Zhengyi Chen, Nathaniel J. Berle, Adrian P. Othon, M. Kay Washington, Shruti A. Anant, Suguru Kurokawa, Victoria H. Ng, Joshua J. Thompson, Justin Jacobse, Jeremy A. Goettel, Ethan Lee, Yash A. Choksi, Ken S. Lau, Sarah P. Short, Christopher S. Williams
Although selenium deficiency correlates with colorectal cancer (CRC) risk, the roles of the selenium-rich antioxidant selenoprotein P (SELENOP) in CRC remain unclear. In this study, we defined SELENOP’s contributions to sporadic CRC. In human single-cell cRNA-Seq (scRNA-Seq) data sets, we discovered that SELENOP expression rose as normal colon stem cells transformed into adenomas that progressed into